ABSTRACT Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. The majority of SUDEP cases occur at night, during sleep, but why this is the case in unclear. It has been proposed that a portion of these cases may be due to lack of adequate supervision during the nighttime and relayed resuscitation efforts following a seizure. Recent evidence suggests this is not the whole story. There are a number of physiologic changes that occur during sleep, that may make sleep relatively intolerant to the additonal physiologic insult of a seizure. Seizure-induced impairment of respiratory, cardiac, and arousal mechanisms have all been implicated in SUDEP. All of these are subject to sleep state-dependent regulation. A large body of evidence suggests that abnormalities in signaling of the neurotransmitter serotonin are important in SUDEP. Serotonin is also regulated in a sleep state-dependent manner, and is involved in the regulation of breathing, cardiac activity, and sleep and wakefulness, and can modulate seizures. The primary goal of this proposal is to understand how seizures that occur during sleep become fatal. In pursuing this goal we will test the overarching hypothesis that serotonin is involved in regulating the state-dependence of seizure-induced death. In Aim 1 we will determine how seizures that occur during sleep dysregulate respiratory function. In Aim 2 we will determine how seizures that occur during sleep dysregulate arousal mechanisms. Finally, in Aim 3 we will determine how REM sleep is protective against seizures. Completion of these aims will provide an understanding of how seizures that occur during sleep could be fatal, and some of the findings could be directly translatable to the clinic to aid in identification of persons at risk for SUDEP and in implemention of novel prophylactic strategies. This work will additionally lay the groundwork for future projects delving deeper into these mechanisms.